Despite the increasing use of optogenetics in vivo, the effects of direct light exposure to brain tissue are understudied. Of particular concern is the potential for heat induced by prolonged optical ...stimulation. We demonstrate that high-intensity light, delivered through an optical fiber, is capable of elevating firing rate locally, even in the absence of opsin expression. Predicting the severity and spatial extent of any temperature increase during optogenetic stimulation is therefore of considerable importance. Here, we describe a realistic model that simulates light and heat propagation during optogenetic experiments. We validated the model by comparing predicted and measured temperature changes in vivo. We further demonstrate the utility of this model by comparing predictions for various wavelengths of light and fiber sizes, as well as testing methods for reducing heat effects on neural targets in vivo.
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•Fiber optic light delivery is sufficient to increase cortical firing rates in vivo•An optogenetics MATLAB package is provided for predicting light and heat spread•In vivo temperature recordings validate model predictions of heat induction
Stujenske et al. demonstrate that light emitted into the brain for optogenetics is sufficient to increase local temperature and the firing rates of single neurons. They provide a software package for modeling light and heat spread from optical fibers.
Theta oscillations synchronize the basolateral amygdala (BLA) with the hippocampus (HPC) and medial prefrontal cortex (mPFC) during fear expression. The role of gamma-frequency oscillations in the ...BLA is less well characterized. We examined gamma- and theta-frequency activity in recordings of neural activity from the BLA-HPC-mPFC circuit during fear conditioning, extinction, and exposure to an open field. In the BLA, slow (40–70 Hz) and fast (70–120 Hz) gamma oscillations were coupled to distinct phases of the theta cycle and reflected synchronous high-frequency unit activity. During periods of fear, BLA theta-fast gamma coupling was enhanced, while fast gamma power was suppressed. Periods of relative safety were associated with enhanced BLA fast gamma power, mPFC-to-BLA directionality, and strong coupling of BLA gamma to mPFC theta. These findings suggest that switches between states of fear and safety are mediated by changes in BLA gamma coupling to competitive theta frequency inputs.
•There are two bands of theta-nested gamma in the BLA during fear expression•BLA cells that phase-lock to fast gamma increase firing during safety•Fast gamma couples to BLA theta during fear and to mPFC theta during safety•mPFC-to-BLA fast gamma directionality indicates safety in three behavioral paradigms
The medial prefrontal cortex is thought to inhibit fear through interactions with the basolateral amygala (BLA). Stujenske et al. show that, during safety, gamma oscillations in the BLA are modulated by medial prefrontal cortex activity, perhaps mediating this inhibition.
Highlights ► Lesion and silencing experiments suggest that the hippocampus and medial prefrontal cortex (mPFC) must cooperate to perform spatial working memory tasks. ► Neural recordings during ...working memory tasks demonstrate enhanced synchronization of the hippocampus and mPFC during spatial working memory. ► Measures of synchrony correlate with learning. ► Individual differences in synchrony may relate to individual differences in behavior in normal subjects and in disease models.
Spatial working memory, the caching of behaviourally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. Although the prefrontal cortex and hippocampus are ...known to contribute jointly to successful spatial working memory, the anatomical pathway and temporal window for the interaction of these structures critical to spatial working memory has not yet been established. Here we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues in mice. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Long-Range Neural Synchrony in Behavior Harris, Alexander Z; Gordon, Joshua A
Annual review of neuroscience,
07/2015, Letnik:
38, Številka:
1
Journal Article
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Long-range synchrony between distant brain regions accompanies multiple forms of behavior. This review compares and contrasts the methods by which long-range synchrony is evaluated in both humans and ...model animals. Three examples of behaviorally relevant long-range synchrony are discussed in detail: gamma-frequency synchrony during visual perception, hippocampal-prefrontal synchrony during working memory, and prefrontal-amygdala synchrony during anxiety. Implications for circuit mechanism, translation, and clinical relevance are discussed.
The medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) functionally interact during innate anxiety tasks. To explore the consequences of this interaction, we examined task-related firing ...of single units from the mPFC of mice exploring standard and modified versions of the elevated plus maze (EPM), an innate anxiety paradigm. Hippocampal local field potentials (LFPs) were simultaneously monitored. The population of mPFC units distinguished between safe and aversive locations within the maze, regardless of the nature of the anxiogenic stimulus. Strikingly, mPFC units with stronger task-related activity were more strongly coupled to theta-frequency activity in the vHPC LFP. Lastly, task-related activity was inversely correlated with behavioral measures of anxiety. These results clarify the role of the vHPC-mPFC circuit in innate anxiety and underscore how specific inputs may be involved in the generation of behaviorally relevant neural activity within the mPFC.
► mPFC neurons differentiate safe and aversive arms in the EPM, an innate anxiety test ► This differentiation is independent of EPM geometry and the anxiogenic stimulus used ► Units locked to ventral hippocampal theta have stronger EPM task-related firing ► The strength of the mPFC representation varies with behavioral anxiety
The mediodorsal thalamus (MD) shares reciprocal connectivity with the prefrontal cortex (PFC), and decreased MD-PFC connectivity is observed in schizophrenia patients. Patients also display cognitive ...deficits including impairments in working memory, but a mechanistic link between thalamo-prefrontal circuit function and working memory is missing. Using pathway-specific inhibition, we found directional interactions between mouse MD and medial PFC (mPFC), with MD-to-mPFC supporting working memory maintenance and mPFC-to-MD supporting subsequent choice. We further identify mPFC neurons that display elevated spiking during the delay, a feature that was absent on error trials and required MD inputs for sustained maintenance. Strikingly, delay-tuned neurons had minimal overlap with spatially tuned neurons, and each mPFC population exhibited mutually exclusive dependence on MD and hippocampal inputs. These findings indicate a role for MD in sustaining prefrontal activity during working memory maintenance. Consistent with this idea, we found that enhancing MD excitability was sufficient to enhance task performance.
22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that ...Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.
Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency ...coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta-prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty.
The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with ...downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.
► Neural activity in the mPFC is more synchronous with ventral than dorsal hippocampus ► Theta-frequency synchrony between the vHPC and mPFC increases with anxiety ► Theta activity in the mPFC correlates with anxiety-related behavior ► mPFC theta increases more strongly in a genetic model of increased anxiety
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